Angiotensin-converting enzyme 2: the first decade

Abstract

The renin-angiotensin system (RAS) is a critical regulator of hypertension, primarily through the actions of the vasoactive peptide Ang II, which is generated by the action of angiotensin-converting enzyme (ACE) mediating an increase in blood pressure. The discovery of ACE2, which primarily metabolises Ang II into the vasodilatory Ang-(1-7), has added a new dimension to the traditional RAS. As a result there has been huge interest in ACE2 over the past decade as a potential therapeutic for lowering blood pressure, especially elevation resulting from excess Ang II. Studies focusing on ACE2 have helped to reveal other actions of Ang-(1-7), outside vasodilation, such as antifibrotic and antiproliferative effects. Moreover, investigations focusing on ACE2 have revealed a variety of roles not just catalytic but also as a viral receptor and amino acid transporter. This paper focuses on what is known about ACE2 and its biological roles, paying particular attention to the regulation of ACE2 expression. In light of the entrance of human recombinant ACE2 into clinical trials, we discuss the potential use of ACE2 as a therapeutic and highlight some pertinent questions that still remain unanswered about ACE2.

Figure 1

Schematic representation of the renin-angiotensin system (RAS). ACE: angiotensin-converting enzyme; ACE2: angiotensin-converting enzyme 2; NEP: neprilysin; AT1R: Ang II type 1 receptor. Angiotensinogen is cleaved by renin in the circulation to generate Ang I. Ang I is cleaved to yield Ang II by ACE, Ang-(1-7) by NEP, or Ang (1-9) by ACE2; this reaction is much less favourable than the production of Ang-(1-7) from Ang II. Ang-(1-9) is then cleaved by either NEP or ACE to yield Ang-(1-7) in a minor pathway. Ang II exerts its main actions by binding to the AT1R. Ang II can also be further cleaved by ACE2, into Ang-(1-7), which exerts its effects through its receptor (Mas). The opposing actions of the two receptors are listed above.

Figure 2

The domain structure and membrane topology of somatic ACE, ACE2, and collectrin. Each protein is a type I integral-membrane protein with an N-terminal ectodomain, a transmembrane region, and a short C-terminal cytoplasmic tail. Residue numbers are indicated. Both ACE and ACE2 contain zinc-binding motifs (HEMGH), which form the active sites of the enzyme: somatic ACE has two active sites whereas ACE2 only has one. Collectrin contains no catalytic residues. ACE2 is homologous to the N-terminal ectodomain of ACE but has no homology with its C-terminal cytoplasmic domain. Instead, it shares a number of residues with the intracellular domain of collectrin. Signal peptide in light grey; transmembrane domain in textured grey.

Figure 3

ACE2 acts as the host cell receptor for SARS-CoV, by binding to the spike protein on the viral capsid. Binding to ACE2 stimulates clathrin-dependent endocytosis of both ACE2 and the SARS-CoV, which is essential for viral infection. Binding of the spike protein to ACE2 induces ADAM 17 activity, thereby reducing the amount of ACE2 expressed on the cell surface. Treatment with soluble ACE-2 or anti-ACE-2 antibodies disrupts the interaction between virus and receptor.